The present invention relates to a medicament useful for medical treatment of human diseases such as thrombotic diseases including lipemia, hypertension and hypotonia which originate in thrombus formation and complications with the thrombotic diseases, and also to a method for the preparation thereof using earthworms as the raw material.
Thrombi are continuously formed in human body but successively dissolved away by the fibrinolytically active enzymes occurring in human body. An imbalance between formation and disappearance of thrombi causes accumulation of unnecessary thrombi resulting in various diseases originating in thrombi. It is a serious problem in recent years that prime and aged persons frequently suffer from various diseases caused by thrombus accumulation such as transient cerebral ischemic attack, cerebral infarction, i.e. cerebral thrombosis or cerebral embolism, ischemic stenocardia, myocardial infarction, arterio-thrombosis, venous thrombo-sis, deep-venous thrombosis, peripheral arterio-obturation, peripheral venous obturation, pulmonary thrombosis, pulmonary embolism and the like.
Therefore, various pharmaceuticals have been developed as a medicament for these diseases among which medicament preparations from a thrombus-resolvent enzyme such as urokinase, streptokinase and the like are effective. Urokinase is particularly highlighted because of the excellent pharmacological activity thereof.
Urokinase is a kind of plasminogen-activators contained in human urine or cultured fetal renal cells and exhibits an effect of thrombus-resolvent by converting plasminogen into plasmin as a fibrinolytic enzyme. However, the direct activation of plasminogen by urokinase is simultaneously accompanied by the side effects of hemorrhage or decrease in the activated partial thromboplastin time due to the decrease of fibrin. Moreover, urokinase has a defect in administration that the patient unavoidably suffers a great pain since urokinase must be administrated by instillation taking 1 to 12 hours in the form of a solution prepared by dissolving, for example, 60,000 to 1,000,000 units of the same in 500 to 1,000 ml of a physiological salt solution or 5% aqueous glucose solution.
On the other hand, streptokinase is produced by the culture of .beta.-hemolytic streptococci and has an activity to indirectly activate plasminogen concurrently with reduction of fibrinogen. Nevertheless, streptokinase has several disadvantages that side effects, such as pyrexia, nausea, headache, convulsion, urticaria, hemorrhage and the like, are caused and, though in rare cases, hypotomia and anaphylaxis are caused, it has an antigenicity and is only poorly effective in the antibody-producing cases and it must be administrated by the intravenous instillation like the aforementioned urokinase.
Apart from the above mentioned situation, earthworms as raw or as dried are known from old times as a kind of Chinese traditional medicines to have various pharmacological activities such as antipyretic, analgesic, diuretic and antidotal effects (see. for example, Tennen Yakubutsu Jiten, page 215, published Apr. 15, 1986, by Hirokawa Publishing Co.).
In recent years, proposals have been made for the use of the extracted effective constituents of earthworms as the thrombus-resolvent prepared by collecting specific fractions obtained in the chromatographic fractionation of the extract solution (see Japanese Patent Kokai 58-14S824, 59-63184 and 59-18413). However, such a product is not practical because the preparation procedure thereof involves very complicated and lengthy treatments of multiple steps in addition to the generally low yield of the product.
Also, the effectiveness of a freeze-dried powder of earthworms for medication of a patient of thrombosis is yet unknown notwithstanding the reported increase in the fibrin-degradation product supposedly derived from dissolved fibrin lumps in the blood of two among six normal persons orally administrated with the powder [Study Reports on Environmental Science B304 - R30, Reports of Specila Research Project of Environmental Science, Part 4, pages 107 to 112, 1986]. Moreover, freeze-dried powders of earthworms must be stored in a cold place of 0.degree. C. or below or with addition of an antiseptic since removal of sundry germs therefrom is always incomplete and still have a problem of denaturation after a long-term storage Acta Haematologica Japonica, volume 45, page 503 (1982)].